Wilms tumor (WT), a pediatric nephroblastoma that occurs with a frequency of 1 in 10,000 births, has been the subject of intense clinical and basic research for several years. The tumor is embryonic in origin, it is detected in children usually during the first 5 years of life and can occur unilaterally or bilaterally. A WT arises when condensed metanephric mesenchymal cells of the developing kidney fail to properly differentiate. The implication of the Wilms tumor 1 (WT1) tumor suppressor gene in the etiology of WT illustrated the impact that genetic alterations can have on both development and tumorigenesis.
Wilms tumor protein I (WT1) is a zinc finger transcription factor expressed during normal ontogenesis such as in fetal kidney, testis and ovary. In adults, WTI expression is limited to low levels on hematopoietic stem cells, myoepithelial progenitor cells, renal podocytes and some cells in testis and ovary. Recent demonstration that WTI is over expressed in several types of leukemia suggested that WTI would be an attractive target for immunotherapy for various cancers.
The Wilms' tumor oncogene protein (WT1) is an attractive target for immunotherapy for leukemias and a wide range of cancers. Peptides derived from the WT1 protein have been identified that induce HLA-A0201-restricted cytotoxic CD8 T cells, capable of killing tumor cells. Two peptides that bind to HLA-A0201 (RMFPNAPYL; SEQ ID NO:56) or HLA-A2402 (CMTWNQMNL; SEQ ID NO:57) have been extensively studied worldwide and have been in clinical trials in patients with leukemia and other solid tumors (Oka et al., Scientific World Journal 2007; 7: 649-665; Mundlos et al. Development 1993; 119:1329-41; Keilholz et al. Leukemia 2005; 19: 1318-1323). These results are encouraging and have provided strong evidence and a rational for therapeutic targeting of the WT1-derived T cell epitopes for leukemias and a wide range of human cancers.
The therapeutic application of the above two WT1-derived peptides is limited to the people who are HLA-A0201, an HLA haplotype found in about 40% of Caucasians and HLA-A2402, a found haplotype in about 40% of Japanese and other Asian populations. Therefore, there is an unmet need for WT1-derived peptides that might be used for most of the world's populations. To extend the therapeutic application in a broader range of population, novel peptides derived from WT1 protein that bind to multiple HLA haplotypes are desired. Such peptides would therefore be capable of stimulating T cells from a larger percentage of the target population, allowing a vaccine strategy that would address a large segment of the population, with durable cytotoxic memory cells.